Development of a comprehensive new endpoint for the evaluation of ...

The 7th Annual Scientific Meeting

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HFSA

S61

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a-Tocopheryl Nicotinate Does Not Improve the Flow-Depended Vasodilation in Patients with Chronic Heart Failure by Duchenne Muscular Dystrophy Taihei Naya,1 Akira Kobayashi1—1Respiratory and Cardiovascular Medicine, National Michikawa Hospital, Iwaki-Machi, Akita, Japan

Development of a Comprehensive New Endpoint for the Evaluation of New Treatments for Acute Decompensated Heart Failure: Results with Levosimendan in the REVIVE 1 Study Milton Packer,1 Wilson S. Colucci,2 Lloyd Fisher,3 Barry M. Massie,4 John R. Teerlink,4 James B. Young,5 Chris J. Garratt6—1Department of Medicine, Columbia University, New York, NY; 2Myocardial Biology, Boston University School of Medicine, Boston, MA; 3Department of Biostatistics, University of Washington, Seattle, WA; 4Department of Medicine, University of California, San Francisco, San Francisco, CA; 5Heart Failure Center, Cleveland Clinic Foundation, Cleveland, OH; 6Cardiovascular Clinical Development, Orion Pharma, Nottingham, United Kingdom

Background: α-Tocopheryl Nicotinate (α-TPN) has been reported to improve the micro-circulatory disturbance experimentally and to make the clinical symptom better. α-TPN is prescribed by neurologists to some patients with Cardiomyopathy by Duchenne Muscular Dystrophy (DMD-CM) in Japan. Recent reports have shown the impaired flow-dependent vasodilation (FDD) in the patients with ischemic Cardiomyopathy. Little information is available on whether FDD is impaired in DMD-CM or whether α-TPN is effective to improve FDD in DMD-CM. Method: FDD was estimated as the hyperemic changes following a brief ischemia in brachial artery diameters (%BAD) and blood flow velocities (%BABV), measured by ultrasonography (FUKUDA UF8900) in 10 DMD-CM patients and 10 agematched controls. Results: %BAD (hyperemic BAD/resting BAD) was significantly depressed in DMD-CM (110.91 ⫾ 2.04% in controls versus 103.90 ⫾ 1.26% in DMDCM, respectively). %BABV (hyperemic BABV/resting BABV) was significantly small in DMD-CM (213 ⫾ 10% in controls versus 171 ⫾ 9% in DMD-CM, respectively). In DMD-CM, %BAD was not significantly improved by α-TPN (104.63 ⫾ 2.11% with α-TPN verses 103.77 ⫾ 2.17% without α-TPN, respectively). %BABV was further smaller in the patients requiring noninvasive positive pressure ventilation. Conclusion: FDD is depressed in DMD-CM. α-TPN does not improve the depressed FDD in DMD-CM. In DMD-CM, the depressed FDD might be not fully associated with the micro-circulatory disturbance. Multiple impacts by respiratory and circulatory disturbances might be important on impaired FDD in DMD-CM.

Traditionally, intravenous (IV) drugs in decompensated heart failure (HF) have been evaluated based on their hemodynamic effects. Thus, no endpoint to measure symptomatic improvement in decompensated HF has yet been validated. To do so, we adapted the clinical composite (which has been validated in trials of chronic HF) to the evaluation of IV levosimendan in a pilot trial of acute decompensated HF (REVIVE-1). A total of 100 patients who were hospitalized for worsening HF and had dyspnea at rest despite IV diuretics were randomized (double-blind) to receive placebo (PBO, n ⫽ 49) or IV levosimendan (LS, n ⫽ 51), given as a loading dose of 12 µg/kg over 10 min and followed by a continuous infusion (0.1 µg/kg/hr for 50 min and 0.2 µg/ kg/hr for 23 hr); patients were then followed closely for 4 additional days. Patients were classified as improved if they reported their HF to be moderately or markedly improved at specific timepoints. Patients were classified as worse if they died or received an IV medication for worsening HF during the 5-day study period. Patients were considered unchanged if they were neither improved nor worse. Different models using different definitions for improvement and worsening were prospectively and retrospectively examined. The initial model defined improvement based on the responses at 24 hr and at 5 days and restricted the definition of worsening to the use of IV vasodilators or inotropic agents. Using this model, improvement was observed more frequently with LS than PBO (49% vs 33%) with no between-group difference in the proportion of patients who were worse (overall P ⫽ 0.229). When the definition of worsening was expanded to include the use of IV diuretics for worsening HF and confined to the occurrence of clinical events, LS-treated patients not only were more likely to show improvement (51% vs 33%) but were less likely to exhibit worsening (20% vs 35%), overall P ⫽ 0.043. When the definition of improvement was expanded to include the responses at 6 hr (in addition to 24 hr and 5 days), the separation between the treatment groups increased even further (improvement in 33% vs 14% and worsening in 24% vs 37%), overall P ⫽ 0.029 (LS vs PBO ). The greater level of improvement in the Clinical Composite on levosimendan was supported by significant reductions in median plasma BNP concentrations compared to placebo at both 24 hours (⫺303 pg/ml vs. ⫺77.5 pg/ml, p ⫽ 0.001) and 5 days (⫺376 pg/ml vs. ⫺99.5 pg/ml, p ⫽ 0.027). These findings indicate that a clinical composite approach can be used to develop an endpoint that distinguishes the effects of IV LS in the setting of acute decompensated HF. The new endpoint is now being used prospectively to evaluate the effects of LS in a definitive second study (REVIVE-2).

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History of Heart Failure and Left Ventricular Ejection Fraction Strongly Predicts Adverse Outcomes among Patients Undergoing Contemporary Percutaneous Coronary Intervention: Insights from TARGET W.H. Wilson Tang,1 David J. Moliterno,1 Gary S. Francis,1 Amy Hsu,1 Marlene Goormastic,1 Eric J. Topol1—1Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH

Nesiritide Added to Standard Care Results in Favorable Reductions in Systolic Blood Pressure and Heart Rate Compared to Standard Care Alone Charles L. Emerman,1 W. Franklin Peacock, IV2 Marc A. Silver,3 on Behalf of the PROACTION Study Group4—1Department of Emergency Medicine, Case Western Reserve University, Cleveland, OH; 2Department of Emergency Medicine, The Cleveland Clinic Foundation, Cleveland, OH; 3Department of Cardiology, Advocate Christ Medical Center, Oak Lawn, IL; 4Scios Inc., Sunnyvale, CA

Background: The prognostic significance of a clinical history of heart failure (HF) and baseline left ventricular ejection fraction (LVEF) in patients undergoing percutaneous coronary intervention with stent implantation and glycoprotein IIb/IIIa inhibitors has not been determined. Methods: In the TARGET study, 4,809 patients undergoing PCI with stent implantation were randomized to tirofiban or abciximab (between December 1999–August 2000). At the time of enrollment, patients were stratified according to the presence of a clinical history of HF and impaired LVEF (⬍50%). Patients were followed for one year for the occurrence of death. Results: The 1-year mortality was higher in HF (n ⫽ 472) compared to non-HF (n ⫽ 4,336) patients (5.1% vs 1.5%, p⬍0.001) and increased with higher NYHA class, but the difference was mainly observed in the LVEF ⬍50% subgroup (n ⫽ 1,122) (see Figure). Although two-thirds of patients with low LVEF or HF were discharged with beta-blockers, only 52% of patients were discharged with ACE inhibitors. Compared to those without beta-blocker at baseline, the 1-year mortality was significantly lower among patients with HF treated with beta-blockers (2.4% vs 9.3%, p ⫽ 0.001). Multivariable logistic regression analysis revealed that baseline clinical history of HF (χ2 ⫽ 11.8, p ⫽ 0.001), and impaired LVEF (χ2 ⫽ 5.2, p ⫽ 0.023) were independent predictors of 1-year mortality. Conclusions: A clinical history of HF and impaired LVEF were associated with increased long-term mortality in patients undergoing percutaneous coronary intervention with stent implantation. In this contemporary study, a large proportion of patients with a history of HF or impaired LVEF remains under-treated with ACE inhibitors, while baseline beta-blocker therapy portends better long-term survival. Early recognition of impaired LVEF and optimal medical therapy with ACE inhibitors and beta-blockers may be important in further improving long-term clinical outcomes in this patient population.

Background: Nesiritide has been shown to be effective in improving clinical symptoms in patients with acutely decompensated heart failure. The PROACTION trial was conducted to determine the safety of using nesiritide early in the Emergency Department (ED). Methods: PROACTION was a multicenter, randomized double blind study. Patients with a history of heart failure, presenting to the ED, requiring observation and IV therapy were enrolled. In addition to standard care (diuretics, O2, and non-IV vasodilators), patients were treated with nesiritide (2 mcg/kg bolus followed by a 0.01 mcg/kg/min infusion) or placebo. Results: Patients with an initial SBP ⫽ ⬎140 who were treated with nesiritide had a 28.7 mm Hg drop over 12 hours compared to an 8.4 mm Hg drop with standard care (p ⬍ 0.001). The differential effect on blood pressure was seen within 1 hour. Patients with an initial SBP between 101 and 139 who were treated with nesiritide had a 12.3 mm Hg drop compared to a 5 mm Hg drop with standard care (p ⬍ 0.017). The differential effect was seen within 30 minutes. Patients with an initial SBP ⬍⫽100 had a 16.7 mmHg increase with standard care and a 1.2 mmHg drop with nesiritide (p ⬍ 0.03). Heart rate decreased slightly in both groups, with a 5% decrease in the nesiritide group at 6 hours vs. a 1% decrease in the placebo group (p ⫽ 0.029). Conclusions: Compared to standard care alone, nesiritide produced favorable decreases in SBP in patients with elevated SBPs while not negatively impacting those patients with low SBPs. Heart rate did not increase consistent with nesiritide’ sattenuation of the sympathetic nervous system. The decrease in pressures is proportional to the baseline pressure, consistent with a low incidence of symptomatichypotension even in patients with low baseline blood pressures. Blood pressure lowering in the most appropriate patients may decrease systemic vascular resistance and other important determinants of myocardial oxygen consumption, which supports the safety and appropriateness of the use of nesiritide in the ED.